Expanding Phenotype of De Novo Mutations in GNAO1: Four New Cases and Review of Literature

Abstract

Mutations in GNAO1 (guanine nucleotide-binding protein, alpha-activating activity polypeptide O) were recently identified as being causative for early epileptic encephalopathy. Since then approximately 27 patients with severe developmental delay and different neurological phenotypes for epilepsy and involuntary movement disorder have been reported. We report four additional patients with mutations in GNAO1 including a report of siblings of different sex harboring the same de novo mutation (c.736G > A, p.Glu246Lys) but showing differences in phenotype with pronounced dystonia in the boy and epilepsy in his sister. Another de novo mutation in GNAO1 (c.607G > A, p.Gly203Arg) was identified in two unrelated girls with severe epilepsy. Both girls later also developed severe dystonia with severe nonepileptic spasms. An extensive review of published cases revealed that epilepsy was reported in only one male patient so far. Thus it appears possible that epilepsy is a sex-dependent phenotypic feature of GNAO1-related diseases.

Keywords

early infantile epileptic encephalopathy - Othahara syndrome - GNAO1 mutation - movement disorders - sex-dependent phenotype

• References

• 1 Wettschureck N, Offermanns S. Mammalian G proteins and their cell type specific functions. Physiol Rev 2005; 85 (04) 1159-1204
• 2 Jiang M, Gold MS, Boulay G. , et al. Multiple neurological abnormalities in mice deficient in the G protein Go. Proc Natl Acad Sci U S A 1998; 95 (06) 3269-3274
• 3 Nakamura K, Kodera H, Akita T. , et al. De Novo mutations in GNAO1, encoding a Gαo subunit of heterotrimeric G proteins, cause epileptic encephalopathy. Am J Hum Genet 2013; 93 (03) 496-505
• 4 EuroEPINOMICS-RES Consortium; Epilepsy Phenome/Genome Project; Epi4K Consortium. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet 2014; 95 (04) 360-370
• 5 Talvik I, Møller RS, Vaher M. , et al. Clinical phenotype of de novo GNAO I mutation: case report and review of literature. Child Neurol Open 2015; 2 (Suppl. 02) 2329048X15583717
• 6 Law C-Y, Chang ST-L, Cho SY. , et al. Clinical whole-exome sequencing reveals a novel missense pathogenic variant of GNAO1 in a patient with infantile-onset epilepsy. Clin Chim Acta 2015; 451 (Pt B): 292-296
• 7 Saitsu H, Fukai R, Ben-Zeev B. , et al. Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay. Eur J Hum Genet 2016; 24 (01) 129-134
• 8 Kulkarni N, Tang S, Bhardwaj R, Bernes S, Grebe TA. Progressive Movement disorder in brothers carrying a GNAO1 mutation responsive to deep brain stimulation. J Child Neurol 2016; 31 (02) 211-214
• 9 Ananth AL, Robichaux-Viehoever A, Kim Y-M. , et al. Clinical course of six children with GNAO1 mutations causing a severe and distinctive movement disorder. Pediatr Neurol 2016; 59: 81-84
• 10 Marcé-Grau A, Dalton J, López-Pisón J. , et al. GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females. Orphanet J Rare Dis 2016; 11: 38
• 11 Yilmaz S, Turhan T, Ceylaner S, Gökben S, Tekgul H, Serdaroglu G. Excellent response to deep brain stimulation in a young girl with GNAO1-related progressive choreoathetosis. Childs Nerv Syst 2016; 32 (09) 1567-1568
• 12 Menke LA, Engelen M, Alders M, Odekerken VJJ, Baas F, Cobben JM. Recurrent GNAO1 mutations associated with developmental delay and a movement disorder. J Child Neurol 2016; 31 (14) 1598-1601
• 13 Sakamoto S, Monden Y, Fukai R. , et al. A case of severe movement disorder with GNAO1 mutation responsive to topiramate. Brain Dev 2017; 39 (05) 439-443
• 14 Arya R, Spaeth C, Gilbert DL, Leach JL, Holland KD. GNAO1-associated epileptic encephalopathy and movement disorders: c.607G>A variant represents a probable mutation hotspot with a distinct phenotype. Epileptic Disord 2017; 19 (01) 67-75
• 15 Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, Kehrer-Sawatzki H. Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum Genet 2013; 132 (10) 1077-1130
• 16 Dibbens LM, Tarpey PS, Hynes K. , et al. X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet 2008; 40 (06) 776-781
• 17 Depienne C, Bouteiller D, Keren B. , et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet 2009; 5 (02) e1000381
• 18 Ram PT, Horvath CM, Iyengar R. Stat3-mediated transformation of NIH-3T3 cells by the constitutively active Q205L Galphao protein. Science 2000; 287 (5450): 142-144
• 19 Garcia-Marcos M, Ghosh P, Farquhar MG. Molecular basis of a novel oncogenic mutation in GNAO1. Oncogene 2011; 30 (23) 2691-2696
• 20 Migliaccio A, Castoria G, Auricchio F. Analysis of androgen receptor rapid actions in cellular signaling pathways: receptor/Src association. Methods Mol Biol 2011; 776: 361-370
• 21 Castoria G, Lombardi M, Barone MV. , et al. Androgen-stimulated DNA synthesis and cytoskeletal changes in fibroblasts by a nontranscriptional receptor action. J Cell Biol 2003; 161 (03) 547-556